Biodefense toxins such as ricin, botulinum neurotoxins, and Shiga toxin are a source of concern for terrorist attacks due to their high toxicity and the limited post-exposure treatment alternatives. Each of these protein toxins exhibits an enzymatic activity that is the basis of its toxicity. Inhalation and ingestion are the primary routes of entry for protein toxins, and once these molecules have entered the cell, treatment options are severely limited. Physical Sciences Inc. (PSI) proposes to develop highly specific binding agents that will inhibit the catalytic activity of botulinum neurotoxins (BoNT). The proposed novel therapeutics will incorporate materials and methods for efficient delivery of the agents to the cytoplasm of target cells thus reversing inhibition of neurotransmitter release. Phase I research will develop novel BoNT inhibitors and demonstrate their efficacy using both in vitro and cell-based assays. In Phase II the agents and delivery vehicles will be optimized and will be tested for their ability to prevent or reverse the effects of BoNT intoxication in live animal models. We anticipate that the proposed system will deliver sufficient quantities of therapeutic to the cytoplasm to increase the LD50 of the agents at least 10-fold and significantly reduce recovery time for BoNT exposure. PUBLIC HEALTH RELEVANCE: Post-exposure treatment options for protein toxins such as ricin and botulinum are limited. This research seeks to develop post-exposure therapies for protein toxin exposure that will greatly improve survival rates. [unreadable] [unreadable] [unreadable]